Resveratrol for Alzheimer's Disease

Alzheimer's Disease Clinical Trial

Official title:

Phase II Study to Evaluate the Impact on Biomarkers of Resveratrol Treatment in Patients With Mild to Moderate Alzheimer's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01504854
• Other study ID #: ADC-037-RES
• Status: Completed
• Phase: Phase 2
• First received: December 23, 2011
• Last updated: September 15, 2014
• Start date: May 2012
• Est. completion date: March 2014

Study information

• Verified date: September 2014
• Source: Alzheimer's Disease Cooperative Study (ADCS)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Resveratrol is derived from plants and is found in highest levels in red wine and the skin of red grapes. A recent study reported that monthly and weekly consumption of red wine is associated with a lower risk of dementia. There is compelling evidence that caloric restriction can improve overall health by activating a class of enzymes known as Sirtuins. Resveratrol is a substance found in some plants that directly activates sirtuins, mimicking the effects of caloric restriction and may affect regulatory pathways of diseases of aging, including Alzheimer's disease (AD).

In this study, people with AD will be given either Resveratrol or placebo for 12 months to determine whether daily resveratrol therapy is beneficial in delaying or altering the deterioration of memory and daily functioning. Subjects age 50 and above with a diagnosis of probable AD may qualify for participation in this study. A small group of 15 participants will be asked to take part in a more detailed 24-hour Pharmacokinetic (PK) sub-study that will measure resveratrol levels over a 24 hour period.

Description:

This double blind, placebo-controlled trial will be conducted at approximately 26 Alzheimer's Disease Cooperative Study (ADCS) clinical centers. One hundred twenty (120) patients with mild to moderate dementia due to probable Alzheimer's disease (AD) will be randomly assigned to treatment (1:1) with resveratrol starting at 500 mg once daily or matching placebo, increasing at 13 week intervals to a maximum of 1 gram twice daily (divided into two 500 mg capsules taken orally) taken with or without food. Participants will be treated for 52 weeks, and will undergo venous blood draws for biomarker analysis at Baseline and at 52 weeks; participants will also undergo two lumbar punctures for biomarker analyses of cerebrospinal fluid (CSF) at Baseline and at Week 52. Participants will undergo magnetic resonance imaging (MRI) to measure rate of whole-brain and regional atrophy at Screening, Week 13 and Week 52 visits. Randomization will be stratified by site. For monitoring of potential toxicities of the study drug - particularly nephrotoxicity - subjects will undergo physical examination, neurological examination, adverse event review, blood chemistries to include blood urea nitrogen (BUN) and Creatinine (Cr), pharmacokinetic (PK) analyses for resveratrol and its metabolites, and urinalysis every 6-7 weeks during the study. Clinical, Cognitive and Functional effects of resveratrol and insulin and glucose metabolism will also be assessed.

A subgroup of approximately 15 subjects enrolled will be randomized 4:1 (N = 15, 12 treated + 3 placebo) for more detailed 24-hour PK analysis. For these individuals, blood samples will be collected at 15 different time points. Measurements will include levels of resveratrol and its major metabolites (sulfated- and glucuronidated-resveratrol). These subjects will complete the detailed PK with each dosage step. This 24-hour PK sampling in the subgroup will occur after the first dose following Baseline, after the first dose at each dose increment (Weeks 13, 26 and 39), and after the final dose (Week 52).

Enrollment will be restricted to individuals who are able to abstain from ingesting large quantities of resveratrol-containing foods (including red wine). 1-2 glasses of red wine or red grape juice and 1 serving of red grapes daily is acceptable. Subjects must also be able to abstain from ingesting herbal/natural preparations or dietary supplements containing resveratrol.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of probable AD (NINDS-ADRDA criteria).

• Age must be 50 years or older.

• Able to ingest oral medications.

• Caregiver/Study Partner who has direct contact with the participant more than 2 days per week to accompany participant to all visits.

• MMSE score between 14 and 26 (inclusive).

• Modified Hachinski score of less than or equal to 4.

• Able to abstain from ingesting large quantities of resveratrol-containing foods (including red wine). 1-2 glasses of red wine or red grape juice daily acceptable; 1 serving of red grapes daily acceptable.

• Able to abstain from ingesting herbal/natural preparations or dietary supplements containing resveratrol.

Exclusion Criteria:

• Non-AD dementia.

• Probable AD with Down syndrome.

• History of clinically significant stroke.

• Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse.

• Sensory impairment that would preclude the participant from participating in or cooperating with the protocol.

• Use of investigational agent within two months of Screening.

• Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratory abnormality.

• Active neoplastic disease, history of cancer five years prior to screening, including breast cancer (history or skin melanoma or stable prostate cancer are not excluded).

• History of seizure within past five years.

• Pregnancy or possible pregnancy.

• Use of resveratrol containing supplements.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Drug:
• Resveratrol
The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).
• Placebo
The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Johns Hopkins University	Baltimore	Maryland
United States	Case Western Reserve University	Beachwood	Ohio
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Baylor College of Medicine	Houston	Texas
United States	University of California, Irvine	Irvine	California
United States	Mayo Clinic, Jacksonville	Jacksonville	Florida
United States	University of Kansas	Kansas City	Kansas
United States	University of California, San Diego - Comprehensive Alzheimer's Program	La Jolla	California
United States	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada
United States	University of Kentucky	Lexington	Kentucky
United States	University of Southern California	Los Angeles	California
United States	Medical University of South Carolina	N. Charleston	South Carolina
United States	Yale University	New Haven	Connecticut
United States	Columbia University	New York	New York
United States	Mount Sinai School of Medicine	New York	New York
United States	New York University	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Banner Alzheimer's Institute	Phoenix	Arizona
United States	Mayo Clinic, Rochester	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	U of WA / VA Puget Sound Alzheimer's Disease Research Center	Seattle	Washington
United States	University of South Florida	Tampa	Florida
United States	Georgetown University	Washington	District of Columbia
United States	Howard University	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Alzheimer's Disease Cooperative Study (ADCS)	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

References & Publications (5)

Albani D, Polito L, Forloni G. Sirtuins as novel targets for Alzheimer's disease and other neurodegenerative disorders: experimental and genetic evidence. J Alzheimers Dis. 2010;19(1):11-26. doi: 10.3233/JAD-2010-1215. Review. — View Citation

Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci. 2011 Jan;1215:161-9. doi: 10.1111/j.1749-6632.2010.05853.x. Review. — View Citation

Smoliga JM, Baur JA, Hausenblas HA. Resveratrol and health--a comprehensive review of human clinical trials. Mol Nutr Food Res. 2011 Aug;55(8):1129-41. doi: 10.1002/mnfr.201100143. Epub 2011 Jun 20. Review. — View Citation

Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MK, Kunz I, Schrauwen-Hinderling VB, Blaak EE, Auwerx J, Schrauwen P. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011 Nov 2;14(5):612-22. doi: 10.1016/j.cmet.2011.10.002. — View Citation

Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One. 2011;6(6):e19881. doi: 10.1371/journal.pone.0019881. Epub 2011 Jun 16. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of change over time on putative biomarkers of AD, particularly CSF total tau, CSF Abeta42, CSF Abeta40, and CSF phospho-tau181		Baseline and Week 52	No
Primary	Inter-arm differences in the assessment of the safety and tolerability of treatment with resveratrol	The safety and tolerability of treatment with resveratrol will be assessed by analysis of adverse events, including symptoms, abnormal findings on physical examinations, standard laboratory tests and PK analysis of resveratrol and its major metabolites. The frequencies of adverse events or laboratory abnormalities between the participants who receive resveratrol and those receiving placebo will be compared.	Baseline, Weeks 6, 13, 19, 26, 32, 39, 45, and 52	Yes
Primary	Change from baseline in volumetric magnetic resonance imaging (MRI)	MRI will be used to assess the effect of treatment on rate of whole brain and hippocampal atrophy as well as regional cortical thinning.	Screening, Weeks 13 and 52	No
Secondary	Change in Mini-Mental State Examination (MMSE)	The MMSE evaluates orientation, memory, attention, concentration, naming, repetition, and comprehension. A lower score indicates more cognitive impairment. The highest score is 30.	Screening, Baseline, Weeks 6, 13, 19, 26, 32, 39, 45 and 52	No
Secondary	Change in Alzheimer's Disease Assessment Scale-Cognitive (ADAScog)	The ADAScog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment and the maximum severity score is 70. A positive change indicates cognitive worsening.	Baseline, Weeks 6, 13, 19, 26, 32, 39, 45, and 52	No
Secondary	Change in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)	The ADCS-ADL is an activities of daily living inventory developed by the ADCS to assess functional performance in participants with AD. The ADCS-ADL includes some items from traditional basic ADL tests (e.g., grooming, dressing, walking, bathing, feeding, toileting) as well as instrumental (complex) activities of daily living (e.g., shopping, preparing meals, using household appliances, keeping appointments, reading). This structured questionnaire is administered to the subject's caregiver/study partner.	Baseline, Weeks 26 and 52	No
Secondary	Change in Clinical Dementia Rating Scale (CDR-SOB)	The CDR is a clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively). The score is based on interviews with the participant and study partner, using a structured interview that assesses six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.	Baseline, Weeks 26 and 52	No
Secondary	Change in Neuropsychiatric Inventory (NPI)	The NPI quantifies behavioral changes in dementia, including depression, anxiety, psychosis, agitation, sleep change, appetite change, and others. This is a structured questionnaire administered to the subject's caregiver/study partner.	Baseline, Weeks 26 and 52	No
Secondary	Comparison of the response to treatment of resveratrol based on ApoE genotype		Baseline	No
Secondary	Changes in cognition, mood, and AD CSF and imaging biomarkers associated with changes in insulin and glucose metabolism	The metabolic indices will be measured and derived from oral glucose tolerance testing prior to and following resveratrol treatment, and relate them to observed changes in cognition, mood, and putative AD biomarkers.	Screening and Week 52	No

External Links

•   Alzheimer's Disease Cooperative Study
•   Alzheimer's Disease Education and Referral (ADEAR) Center. The ADEAR Center is a service of the National Institute on Aging (NIA).